Notch signaling defines an evolutionary conserved cell interaction mechanism, controlling the acquisition of cell fates throughout development. The malfunction of Notch leads to a broad spectrum of developmental abnormalities in metazoans including pathologic conditions in humans. The goal of this proposal is the dissection of this signaling mechanism at a molecular and genetic level using both Drosophila as well as mammalian cell culture as our experimental systems. We wish to gain insight on how Notch signals integrate with existing cellular factors to dictate cell fates in such an extraordinarily broad spectrum of cells. We intend to take a multidisciplinary approach in addressing the subject. We propose a series of genetic studies aimed in identifying and characterizing modulators of Notch signals and biochemical analyses designed to explore the biochemical nature of Notch signaling pathway elements and define molecular partners. We are also proposing to use expression analysis based on microarray technology we have set up, to examine the underlying transcriptional complexity of Notch signals in specific developmental contexts. Finally we will use chemical screening approaches to identify small molecule modulators of Notch activity.